Post-traumatic stress disorder (PTSD) and autism-spectrum disorders (ASD) are marked by persistent and intense contextual fear and anxiety that are often caused (PTSD) or notably exacerbated (ASD) by acute social stress. Social support, on the other hand, significantly reduces fear and anxiety symptoms in both disorders. The brain mechanisms underlying different effects of social stimuli on emotional processes, and specifically on the enhancement and reduction of learned fear are not known. Here we propose to identify, at a cellular and molecular level, the neurotransmitter receptors and post-receptor signal transduction pathways by which positive and negative social interactions affect acquired contextual fear. The glutamatergic and oxytocinergic systems, acting via metabotropic glutamate receptors 5 (mGluR5) and oxytocin receptors (Oxtr), respectively, are potently activated during social interactions and co-regulate social behavior. However, the delayed effects of mGluR5 and Oxtr on affective processes markedly differ: the adverse effects of mGluR5 predominate after negative, whereas the beneficial effects of Oxtr prevail after positive social interactions. mGluR5 and Oxtr are similarly distributed in the brain but may differentially couple to guanine nucleotide-binding (G)-proteins. We therefore hypothesize that the mechanisms underlying different actions of mGluR5 and Oxtr are at a post-receptor, signal transduction level. We recently developed social defeat and social buffering paradigms to model the opposite effects of negative and positive social interactions on emotion and establish: (1) How social defeat and social buffering affect signal transduction and contextual fear conditioning;(2) What is the contribution of mGluR5 and Oxtr to these effects;and (3) Which protein kinases downstream of mGluR5- and Oxtr mediate the effects of social interactions on fear. mGluR5 and Oxtr are highly expressed in the lateral septum (LS). This area plays a prominent role in processing social interactions and modulates the action of hippocampal output fibers required for contextual fear conditioning. On this basis, we propose that signaling within LS neurons receiving hippocampal input will reveal novel molecular actions of mGluR5 and Oxtr relevant for fear regulation. Our central hypothesis posits that, within the LS, mGluR5 and Oxtr activate discrete subsets of G-protein coupled protein kinase pathways mediating the disparate effects of social defeat and social buffering on fear. After completing this program we expect to have identified: (i) the cellular and molecular mechanisms by which mGluR5 and Oxtr activate signal transduction in response to negative and positive social interactions;and (ii) the contribution of these mechanisms to regulation of fear. Targeting selected protein kinases among a multitude of receptor-activated pathways will increase the specificity while minimizing side effects of emerging treatments for fear symptoms in PTSD and ASD. PUBLIC HEALTH RELEVANCE: Acute social stress exacerbates fear and anxiety in patients with post-traumatic stress (PTSD) and autism- spectrum disorders (ASD). Social support, on the other hand, may significantly prevent the occurrence of these symptoms. We propose to discover the molecular mechanisms by which negative and positive social interactions exert opposite effects on fear, and thus identify novel treatment targets PTSD and ASD.